PROJECT SUMMARY I will study the mechanisms that underlie a health disparity and vulnerability to systemic fungal disease in the Hmong population. People of Hmong descent are 10 to 100 times more likely than non-Asian peers to acquire blastomycosis (an infection due to Blastomcyes dermatitidis) despite having fewer behavioral risk factors or co- morbidities. Blastomycosis, like other invasive mycoses, produces severe illness in some racial and ethnic groups, prompting the idea that genetic polymorphisms govern susceptibility. None have been found and this represents a gap in knowledge. My lab sequenced the whole genomes of 5 Hmong blastomycosis patients involved in an epidemic in Wisconsin. We found 192 single-nucleotide polymorphisms (SNPs) shared in the patients, rare in the European Super Population, and meeting additional criteria such as location in an annotated regulatory region. Notably, many of the SNPs are in or near the gene encoding IL-6 or other genes that nurture IL-17 immunity. IL-17 is important in controlling fungal infection, but also in development of autoimmunity. I will test the hypothesis that SNPs in IL-6 and related genes underlie immune dysregulation in the Hmong patients. My first aim is to study how SNPs identified in the pilot cohort impact the regulation of IL-6. As pathology may arise from either weak or over-exuberant responses, any difference in the response between Hmong patients and controls may be significant. SNP(s) that account for the observed differences will be identified by genetically manipulating primary cells and reporter cells, then studying impact on function. Another goal of the first aim is to investigate the function of an unstudied long non-coding RNA (lncRNA) that overlaps the IL-6 gene; it is likely that this lncRNA regulates IL-6 production. I postulate that a SNP we identified in this lncRNA modifies its function and thus impacts IL-6 transcript and product. My second aim is to apply two unbiased, open-ended methods to probe the anti-fungal responses of circulating immune cells from Hmong blastomycosis patients and controls. In these studies, cells will be probed with defined ligands or yeast, and response will be measured by cytokine bead array and transcriptome analysis. These data will reveal if receptors or signaling pathways are functioning aberrantly. In addition to supporting mechanistic findings from Aim 1, these studies will help generate new hypotheses. This proposal addresses a key gap in knowledge: the mechanism that underlies a documented health disparity. Similar work on tuberculosis has identified SNPs that predict response to treatment, which allows clinicians to tailor therapy to individual patients. My results will similarly facilitate precise medical decision-making. My findings may also have implications beyond the field of fungal immunology; other IL-17-mediated diseases include autoimmune disorders and cancer. I am excited to undertake this project, and know that the training I receive in pursuing my aims will prepare me for a fruitful career as a clinician-scientist in Infectious Disease.